PDGFRβ Expression and Function in Fibroblasts Derived from Pluripotent Cells is Linked to DNA Demethylation

Hewitt, Kyle J.; Shamis, Yulia; Knight, Elana B.; Smith, Avi; Maione, Anna G.; Alt-Holland, Addy; Sheridan, Steven D.; Haggarty, Stephen J.; Garlick, Jonathan A.

doi:10.1242/jcs.099192

Cited by 29 publications

(18 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…All three inhibitors have a common kinase target, PDGFR. It has been shown that blockade of PDGFR impairs the ability of embryonic stem cells to assemble 3D extracellular matrix, most likely due to decreased expression of matrix proteins including collagen and fibronectin (33). However, we show that downregulation of PDGFR does not mimic the cell death effect of sunitinib, suggesting that different kinases are needed or alternatively that downstream mediators of cell viability are activated in a 3D environment, likely through focal adhesions proteins.…”

Section: Discussioncontrasting

confidence: 62%

Culture Dimensionality Influences the Resistance of Glioblastoma Stem-like Cells to Multikinase Inhibitors

Fernandez-Fuente

Mollinedo

Grande

et al. 2014

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Sunitinib, an inhibitor of kinases, including VEGFR and platelet-derived growth factor receptor (PDGFR), efficiently induces apoptosis in vitro in glioblastoma (GBM) cells, but does not show any survival benefit in vivo.One detrimental aspect of current in vitro models is that they do not take into account the contribution of extrinsic factors to the cellular response to drug treatment. Here, we studied the effects of substrate properties including elasticity, dimensionality, and matrix composition on the response of GBM stem-like cells (GSC) to chemotherapeutic agents. Thirty-seven cell cultures, including GSCs, parenchymal GBM cells, and GBM cell lines, were treated with nine antitumor compounds. Contrary to the expected chemoresistance of GSCs, these cells were more sensitive to most agents than GBM parenchymal cells or GBM cell lines cultured on flat (twodimensional; 2D) plastic or collagen-coated surfaces. However, GSCs cultured in collagen-based threedimensional (3D) environments increased their resistance, particularly to receptor tyrosine kinase inhibitors, such as sunitinib, BIBF1120, and imatinib. Differences in substrate rigidity or matrix components did not modify the response of GSCs to the inhibitors. Moreover, the MEK-ERK and PI3K-Akt pathways, but not PDGFR, mediate at least in part, this dimensionality-dependent chemoresistance. These findings suggest that survival of GSCs on 2D substrates, but not in a 3D environment, relies on kinases that can be efficiently targeted by sunitinib-like inhibitors. Overall, our data may help explain the lack of correlation between in vitro and in vivo models used to study the therapeutic potential of kinase inhibitors, and provide a rationale for developing more robust drug screening models. Mol Cancer Ther; 13(6); 1664-72. Ó2014 AACR.

show abstract

Section: Discussioncontrasting

confidence: 62%

Culture Dimensionality Influences the Resistance of Glioblastoma Stem-like Cells to Multikinase Inhibitors

Fernandez-Fuente

Mollinedo

Grande

et al. 2014

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…S1; ref. 21). We also did not find cells expressing CD117, a putative marker of luminal progenitor cells ( Supplementary Fig.…”

Section: Normal Breast Contains Multiple Subpopulations Of Cellsmentioning

confidence: 67%

Dual TGFβ/BMP Pathway Inhibition Enables Expansion and Characterization of Multiple Epithelial Cell Types of the Normal and Cancerous Breast

Prasad

Kumar

Bhat‐Nakshatri

et al. 2019

Molecular Cancer Research

View full text Add to dashboard Cite

Functional modeling of normal breast epithelial hierarchy and stromal-epithelial cell interactions have been difficult due to inability to obtain sufficient stem-progenitor-mature epithelial and stromal cells. Recently reported epithelial reprogramming assay has partially overcome this limitation, but cross-contamination of cells from the feeder layer is a concern. The purpose of this study was to develop a feeder-layerindependent and inexpensive method to propagate multiple cell types from limited tissue resources. Cells obtained after enzymatic digestion of tissues collected at surgery or by coreneedle biopsies were plated on tissue culture dishes precoated with laminin-5-rich-conditioned media from the rat bladder tumor cell line 804G and a defined growth media with inhibitors of ROCK, TGFb, and BMP signaling. Cells were characterized by flow cytometry, mammosphere assay, 3D cultures, and xenograft studies. Cells from the healthy breasts included CD10 þ /EpCAM À basal/myoepithelial, CD49f þ /EpCAM þ luminal progenitor, CD49f À /EpCAM þ mature luminal, CD73 þ /EpCAM þ /CD90 À rare endogenous pluripotent somatic stem, CD73 þ /CD90 þ /EpCAM À , estrogen receptor alpha-expressing ALCAM (CD166) þ /EpCAM þ , and ALDFLUOR þ stem/luminal progenitor subpopulations. Epithelial cells were luminal (KRT19 þ ), basal (KRT14 þ ), or dual-positive luminal/basal hybrid cells. While breast cells derived from BRCA1, BRCA2, and PALB2 mutation carriers did not display unique characteristics, cells from women with breast cancer-protective alleles showed enhanced differentiation. Cells could also be propagated from primary tumors and metastasis of breast, ovarian, and pancreatic cancerneuroendocrine subtype. Xenograft studies confirmed tumorigenic properties of tumor-derived cells.Implications: Our method expands the scope of individualized studies of patient-derived cells and provides resources to model epithelial-stromal interactions under normal and pathologic conditions.

show abstract

“…As well as the growth of adipocytes, infiltration of a blood vessel network and a mild macrophage response into all Adipogel implants, we also observed a significant uniform infiltration of connective tissue cells that were universally PDGFR β ‐positive. PDGFR β is strongly associated with the maturation of mesenchymal cells (Hewitt et al ., ). The production of platelet derived growth factor‐BB (PDGF‐BB) by endothelial cells recruits PDGFR β ‐positive mesenchymal cells that migrate from the interstitium to wrap abluminally around capillaries, forming the pericytes of the capillary wall (Benjamin et al ., ; Darland and D'Amore, ).…”

Section: Discussionmentioning

confidence: 97%

An adipogenic gel for surgical reconstruction of the subcutaneous fat layer in a rat model

Debels

Gerrand

Poon

et al. 2015

J Tissue Eng Regen Med

View full text Add to dashboard Cite

'Off-the-shelf' tissue-engineered skin alternatives for epidermal and dermal skin layers are available; however, no such alternative for the subdermal fat layer exists. Without this well-vascularized layer, skin graft take is variable and grafts may have reduced mobility, contracture and contour defects. In this study a novel adipose-derived acellular matrix (Adipogel) was investigated for its properties to generate subdermal fat in a rat model. In a dorsal thoracic site, a 1 × 1 cm Adipogel implant was inserted within a subdermal fat layer defect. In a dorsal lumbar site, an Adipogel implant was inserted in a subfascial pocket. Contralateral control defects remained empty. At 8 weeks wound/implant sites were evaluated histologically, immunohistochemically and morphometrically. Identifiable thoracic Adipogel implants lost volume in vivo over 8 weeks. Neovascularization and adipogenesis were evident within implants and adipocyte percentage volume was 33.07 ± 6.55% (mean ± SEM). A comparison of entire cross-sections of thoracic wounds demonstrated a significant increase in total wound fat in Adipogel-implanted wounds (37.19 ± 4.48%, mean ± SEM) compared to control (16.53 ± 4.60%; p = 0.0092), indicating that some Adipogel had been completely converted to normal fat. At the lumbar site, Adipogel also lost volume, appearing flattened, although fat generation and angiogenesis occurred. At both sites macrophage infiltration was mild, whilst many infiltrating cells were PDGFRβ-positive mesenchymal cells. Adipogel is adipogenic and angiogenic and is a promising candidate for subcutaneous fat regeneration; it has the potential to be a valuable adjunct to wound-healing therapy and reconstructive surgery practice. Copyright © 2015 John Wiley & Sons, Ltd.

show abstract

PDGFRβ Expression and Function in Fibroblasts Derived from Pluripotent Cells is Linked to DNA Demethylation

Cited by 29 publications

References 47 publications

Culture Dimensionality Influences the Resistance of Glioblastoma Stem-like Cells to Multikinase Inhibitors

Culture Dimensionality Influences the Resistance of Glioblastoma Stem-like Cells to Multikinase Inhibitors

Dual TGFβ/BMP Pathway Inhibition Enables Expansion and Characterization of Multiple Epithelial Cell Types of the Normal and Cancerous Breast

An adipogenic gel for surgical reconstruction of the subcutaneous fat layer in a rat model

Contact Info

Product

Resources

About